Tests for local toxicity of intramuscular drug preparations: comparison of in vivo and in vitro methods.

Different concentrations of aqueous preparations of metoclopramide, gaboxadol, cis(Z)-clopenthixol, digoxin and chlorpromazine and of cis(Z)-clopenthixol acetate in Viscoleo have been tested for local toxicity after intramuscular injection in rabbits. The weight of macroscopically changed muscle tissue isolated 3 days after injection was determined. In addition, homogenized injection site muscle tissue was analysed for creatine kinase (CK) activity and by comparison with the CK activity of contralateral muscle tissue, the amount of injection site muscle tissue totally depleted for CK activity was calculated. The substances have also been tested for in vitro toxicity. The concentrations of the substances which caused 100% haemolysis of human erythrocytes or minimal cytotoxicity in cell culture assays using MRC-5 fibroblasts were estimated. Metoclopramide and gaboxadol caused no or only minimal local muscle damage in the rabbits. Metoclopramide caused local bleeding. The four other substances caused concentration-dependent muscle damage. Although there was some deviations, the two in vitro tests reflected reasonably well the in vivo findings. The results of this study suggest that the in vitro tests employed can be useful as screening tests for local toxic effect of intramuscular drug preparations. However, further studies are required before conclusion as to predictability can be drawn. The in vitro methods are inexpensive and quick, especially the haemolysis test.